More than 500,000 people in United States have end stage renal disease (ESRD). These individuals suffer from an extremely high incidence of cardiovascular (CV) death, but treatments effective in reducing CV mortality in the general population are less efficacious in dialysis-dependent ESRD, and new therapies are needed. The disappointing results with standard therapies appear to be attributable to differences in the mechanisms underlying CV disease in ESRD. Sudden death accounts for the vast majority of CV deaths in individuals with ESRD, with a 5-folder higher frequency than atherosclerotic death or myocardial infarction which account for a higher proportion of CV mortality in other settings. Targeting ESRD-specific mechanisms for sudden CV death rather than the mechanisms underlying atherosclerosis and myocardial infarction may thus be a particularly potent way to improve CV outcomes in ESRD, but there are currently no well-established targets or therapies for this purpose. A wealth of data including studies by the applicants demonstrate that myocardial fibrosis and microvascular dropout are dramatically increased in the hearts of individuals with ESRD, and that non-invasive measures of myocardial fibrosis and microvascular disease are highly predictive of CV death, suggesting that they are important determinants of sudden CV death. Additional studies suggest that low bioavailability of nitric oxide (NO) and secondary increases in circulating inhibitors of angiogenesis are critical and synergistic contributors to progression of myocardial pathology. Combination therapy with the NO donor isosorbide dinitrate (ISD) and hydralazine (HY) increases NO bioavailability, limits nitrate tolerance, and decreases mortality in black patients with heart failure, but it has not bee tested in ESRD. We hypothesize that NO deficiency and secondary changes in related angiogenesis inhibitors contribute to the progression of myocardial fibrosis and capillary rarefaction in ESRD and that use of ISD/HY in hemodialysis patients will inhibit myocardial fibrosis and microvascular loss. This proposal will generate pilot data in humans confirming the associations of NO and related angiogenesis inhibitors with adverse changes in myocardial histology. We will test our aims by analyzing atrial appendages and blood previously collected from patients undergoing cardiac surgery and with a pilot trial comparing combination ISD/HY with amlodipine in chronic hemodialysis patients. This trial will generate preliminary safety and tolerability data for the combination and will assess whether combined ISD/HY improves myocardial fibrosis and microvascular supplying measured using tissue Doppler Echocardiography and myocardial perfusion imaging (PET) scans, respectively. Chronic dialysis patients have a high incidence of CV death despite the expenditure of nearly 10% of Medicare funding on their care. This project will improve understanding of important pathways contributing to CV death in ESRD and will test whether a targeted therapy favorably impacts the underlying mechanisms and has the potential to reduce CV mortality in a growing, high-risk population.